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Expert Review ajog.org

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Nonsteroidal antiinflammatory drug resistancein dysmenorrhea: epidemiology, causes,and treatmentFolabomi A. Oladosu, PhD; Frank F. Tu, MD, MPH; Kevin M. Hellman, PhD

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Although nonsteroidal antiinflammatory drugs can alleviate menstrual pain, about 18% ofwomen with dysmenorrhea are unresponsive, leaving them and their physicians topursue less well-studied strategies. The goal of this review is to provide a background fortreating menstrual pain when first-line options fail. Research on menstrual pain andfailure of similar drugs in the antiplatelet category suggested potential mechanismsunderlying nonsteroidal antiinflammatory drug resistance. Based on these mechanisms,alternative options may be helpful for refractory cases. This review also identifies keypathways in need of further study to optimize menstrual pain treatment.

Key words: adenomyosis, endometriosis, menstrual pain, nonsteroidal antiinflammatorydrugs, oral contraception, primary dysmenorrhea, secondary dysmenorrhea

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IntroductionThe scope of the clinical problem ofmenstrual pain was effectively commu-nicated by former First Lady MichelleObama, when she tweeted, “Why aregirls still missing so many days of schoolbecause of their menstrual cycles?”1 Toomany women hide this personal stigma,and experience a physical and psycho-logical burden of frequent, severelypainful cramps occurring over severaldays every month, persisting for decades.The transcultural impact of this problemwas highlighted when Chinese Olympicmedalist Fu Yuanhui acknowledged thatmenstrual pain affected her Olympicswimming performance.2 The etiologyof menstrual pain remains inadequatelycharacterized,3 and this limited scientificunderstanding hinders adequate treat-ment for women who are unresponsiveto first-line options including nonste-roidal antiinflammatory drug (NSAID)therapy. To optimize the managementof menstrual pain, further studies ofits pathophysiology are needed. This

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From the Department of Obstetrics andGynecology, NorthShore UniversityHealthSystem and Pritzker School of MedicineUniversity of Chicago, Evanston, IL.

Received May 29, 2017; revised Aug. 14, 2017;accepted Aug. 31, 2017.

supported by Eunice Kennedy Shriver NationalInstitute of Child Health and HumanDevelopment HD081709, National Institute ofDiabetes and Digestive and Kidney DiseasesDK100368, and NorthShore UniversityHealthSystem.

F.F.T. was a consultant for AbbViePharmaceuticals. The remaining authors reportno conflict of interest.

Corresponding author: Kevin M. Hellman, [email protected]

0002-9378/$36.00ª 2017 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.ajog.2017.08.108

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review summarizes current scientificknowledge and associated critical gaps inmenstrual pain unresponsive to NSAIDs(Figure 1).

Epidemiology of NSAID-resistantdysmenorrheaMenstrual pain, also known as dysmen-orrhea, is common and affects nearlyhalf of reproductive-age girls andwomen.4-6 Before the advent of NSAIDtherapy, it was observed that 10% of highschool girls in Los Angeles missed classesbecause of dysmenorrhea.7 The devel-opment of NSAIDs in 1969 heralded anew era of pain management, and over-the-counter availability of this medica-tion class in 1983 held the promise ofresolving dysmenorrhea for manywomen. Indeed, for most women,NSAIDs are effective for treatingdysmenorrhea as demonstrated by ameta-analysis of 35 randomizedcontrolled trials.8 However, dysmenor-rhea still causes 10-20% of US femalehigh school students to miss class duringtheir menses.9,10 This phenomenon isalso seen internationally,11 with men-strual pain-induced absenteeism occur-ring at similar or greater rates.12-14

Further, a review of 51 different clinicaltrials found that 18% of women reportminimal or no relief of menstrual pain

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with NSAIDs.15 This failure to relievepain suggests multiple pathologicalmechanisms may contribute to treat-ment unresponsiveness. Clarifying thesemechanisms is an obvious critical needin gynecological research.

What causes menstrual pain?Preclinical research studies suggestprostaglandin (PG)-dependent mecha-nisms drive dysmenorrhea in a majorityof women (reviewed by Maia et al16 in2005). The start of menstruation ismarked by the simultaneous decrease incirculating progesterone and estradiol,initiating increased transcription ofendometrial collagenases, matrix metal-loproteinases (MMPs), and inflamma-tory cytokines (Figure 2). Up-regulatedMMPs specifically target and breakdown endometrial tissue, freeing phos-pholipids from the cellular membrane.Uterine phospholipases convert availablephospholipids to arachidonic acid,which is then synthesized into PG,prostacyclins, and thromboxane-2a viacyclooxygenase (COX)-1 and COX-2.Notably, COX-2 expression is highestduring menses.16 Although it is unclearwhether increased COX-2 expressionoccurs in dysmenorrhea, the end prod-ucts PGE2 and PGF2a are elevated in themenstrual effluent in dysmenorrheic

American Journal of Obstetrics & Gynecology 1

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FIGURE 1---

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Proposed pathway examining nonsteroidal antiinflammatory drug (NSAID)-resistant dysmenorrhea.

Many complex mechanisms contribute to development of NSAID-resistant dysmenorrhea. NSAIDs

normally reduce menstrual pain via suppression of peripheral and systemic prostaglandins (PG) and

corresponding downstream effects (shown in black). Elements on left branch highlight uterine

mechanisms while right branch highlights central and peripheral neural mechanisms. Various

physiological factors, ranging from poor medical adherence to involvement of PG-independent

cascades, may disrupt NSAID efficacy to ameliorate menstrual pain and promote NSAID resis-

tance (shown in red).

COX, cyclooxygenase; CYP, cytochrome P450.

Oladosu. NSAID-resistant dysmenorrhea. Am J Obstet Gynecol 2017.


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women when compared to healthycontrols.17,18

The identification of elevated PGE2and PGF2a in dysmenorrhea supportedthe strategy of inhibiting COX-2 with

2 American Journal of Obstetrics & Gynecology M

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NSAIDs to treat menstrual pain.Nonspecific NSAIDs (Table) bind toboth COX-1 and COX-2 to inhibit PGsynthesis. More selective NSAIDs knownas COX-2 inhibitors alleviate menstrual

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pain by specifically inhibiting COX-2activity. Unlike COX-1, which is consti-tutively expressed, COX-2 is up-regulated by stimuli associated withinflammation19 and during progester-one withdrawal,20,21 thus making COX-2 inhibitors an appropriate alternativeto nonspecific NSAIDs.

Although it is possible that PGs couldexcite nociceptors and cause pain, it isbelieved that PGs indirectly causecramping pain by stimulating uterinecontractility.22 Preclinically, we recentlyconfirmed that PGF2a administrationincreases uterine contractility and elicitsvisceral pain.23 Conversely, drugs thatinhibit PG synthesis, such as ibuprofen24

and naproxen,25 reduce uterine contrac-tility in dysmenorrheic women. Thesefindings suggest that PGs increase uterinecontractility and produce cramping painvia temporary elevations in uterine pres-sure.22 Since not all women withdysmenorrhea have alterations in uterinepressure,26 other mechanisms mightcontribute to menstrual pain. Forexample, impaired uterine perfusion wasobserved in dysmenorrhea27; ischemiamay also cause cramping pain. In ourmousemodel of dysmenorrhea, impaireduterine perfusion and hypoxemia alsooccurred.23 Although these studiescollectively suggest physiological mecha-nisms underlying dysmenorrhea, they failto clarify why some women do notrespond to NSAIDs.

Anatomical factorsA subset of women with dysmenorrhea,particularly those with delayed presen-tation after menarche, may harborseparate contributing anatomical factorssuch as endometriosis, leiomyoma, oradenomyosis; these cases are examples of“secondary dysmenorrhea” that couldunderlie NSAID resistance. Undoubt-edly, surgical interventions for thesestructural issues address dysmenorrhea.For example, in a meta-analysis, lapa-roscopic excision of endometriosis wasshown to reduce menstrual pain.28 Themolecular contributions of anatomicalfactors to secondary dysmenorrhea arelimited. Immunohistological studiesinvestigating endometriosis demon-strated that lesions have increased

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FIGURE 2---

Production of prostaglandins (PG) via onset of menstruation. Decreased progesterone and estrogen

levels at end of luteal phase initiate cascade that results in breakdown of endometrial tissues, release

of cellular phospholipids, and subsequent production of PG.

COX, cyclooxygenase; MMP, matrix metalloproteinases; NSAID, nonsteroidal antiinflammatory drug; TX, thromboxane.


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COX-2 expression,29 which led to cor-responding increased PG30 and aroma-tase activity.31 Ectopic endometriumfrom adenomyosis patients expressedincreased levels of transient receptorpotential vanilloid 1 (a pain signalingprotein) and oxytocin receptor.32 Geneexpression of myometrial regulatorsmyostatin and MMP14 from leiomyomabiopsies were positively correlated tosevere dysmenorrhea.33 These in vitrostudies provide insight into mechanismsthat promote secondary dysmenorrhea,but more research is needed to unmaskthe complex pathophysiology associatedwith these anatomical factors.

The causal contribution of anatomicalfactors to dysmenorrhea, particularlythose that exhibit NSAID unrespon-siveness, is unclear. A meta-analysisestimated as many as 29% of dysmen-orrheic women may have moderate tosevere endometriosis.34 However, sincemany women do not undergo laparo-scopic evaluation, it is difficult to identifythe proportion of women with NSAID-resistant dysmenorrhea who have endo-metriosis. A small clinical study foundthat among 31 women with NSAID-resistant dysmenorrhea, 35% hadendometriosis.35 In a larger study (n ¼654), 25% of participants with NSAID-resistant dysmenorrhea had ultrasoundor magnetic resonance imaging sugges-tive of endometriosis.36 Conversely, it isimportant to note that dysmenorrheasymptoms are nonspecific for endome-triosis,37 and NSAIDs can be effective inrelieving some cases of menstrual pain inwomen with endometriosis.38,39 In oneobservational study of leiomyomas, 70%of women with fibroids used NSAIDsand 51% reported a reduction in symp-toms.40 It is uncertain whether NSAIDsare useful for adenomyosis.41 Since it isunknown whether anatomical factorscontribute to NSAID unresponsiveness,further research is needed to determinewhether treatment strategies targetinganatomical factors are sufficient foraddressing the causes of NSAID-resistant dysmenorrhea.

Molecular mechanismsTherapeutic alternatives for NSAID-resistant dysmenorrhea will be

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developed quicker once mechanisticcharacterization progresses. NSAIDscollectively elicit nonspecific inhibitionof COX isoforms (Table). COX-1 andCOX-2 are homologous, share 63%identical amino acid sequences and havea similar catalytic binding site.19

Although NSAIDs bind nonselectivelyto both COX isoforms, they vary inisoform-specific inhibition. As seen inthe Table, NSAIDs such as aspirin andibuprofen are more selective for COX-1,while diclofenac preferentially targetsCOX-2.42 Genetic polymorphisms wereshown to disrupt COX-1 inhibition withaspirin. For example, Ulehlova et al43

demonstrated that COX-1 poly-morphism rs10306114 was correlatedwith high platelet aggregation in aspirin-resistant individuals. Although multiplesingle nucleotide polymorphisms(SNPs) that contribute to aspirin resis-tance were identified, they were onlyreplicated in some studies and remain anactive area of research (reviewed by

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Weng and colleagues44). Although thereare no documented COX poly-morphisms directly associated withNSAID binding, there are several COXSNPs within the promoter regions thatmay alter NSAID efficacy.45 Notably,rs20417 is a SNP in the promoter regionof COX-2 associated with aspirin resis-tance.41 Further research is needed todetermine if the identified SNPs have atranscriptional effect contributing toNSAID-resistant dysmenorrhea.

Another molecular factor that con-tributes to treatment resistance is drugbioavailability. The drug formulationalongside an individual’s metabolicprofile may alter the efficacy of bothantiplatelet and NSAID therapy. Onestudy found a significant relationshipbetween total naproxen serum levels anda reduction in rheumatoid arthritissymptoms46; the range of oral dosagesused (250, 500, and 1500 mg), however,makes it difficult to determine whethervariable absorption significantly


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TABLECommonly used nonsteroidalQ5 antiinflammatory drugs andconcentrations that inhibit cyclooxygenase activity in blood

NSAID COX-1 IC50, mmol/L COX-2 IC50, mmol/L COX-1:COX-2 IC50 ratioa

Diclofenac 0.26 0.01 0.05

Aspirin 4.45 13.88 3.12

Ketorolac 0.27 0.18 0.68

Naproxen 32.01 28.19 0.88

Ibuprofen 5.90 9.90 1.69

COX, cyclooxygenase; NSAID, nonsteroidal antiinflammatory drug.

a Ratios >1 indicate drug is more selective for COX-1 and ratios <1 indicate drug is more selective for COX-2.



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contributed to inadequate pain relief.Other mechanisms affecting NSAIDmetabolism could also greatly impactCOX inhibition. Cytochrome P450(CYP) enzymes, specifically CYP1A2,CYP2C8, and CYP2C9, are responsiblefor metabolizing NSAIDs. CYP gain-of-function variants are associated withincreased metabolism, resulting indecreased drug effect.47 For example, theCYP2C9*2/*2 polymorphism was asso-ciated with increased total clearance ofcelecoxib and diclofenac.48 Moreresearch is necessary to determine ifother gain-of-function variants exist andalter NSAID metabolism.

Other molecular contributors toNSAID-resistant dysmenorrheaIn addition to COX and PG-mediatedpathways, other molecular mechanismscould drive NSAID-resistant dysmenor-rhea. Leukotrienes, a class of eicosanoidssynthesized via 5-lipoxygenase, shouldbe considered candidate mediators,49 astheir increased expression is found in theendometrium,50 urine,51 and menstrualeffluent52 of womenwith dysmenorrhea.However, leukotriene receptor inhibi-tion did not successfully alleviatemenstrual pain.53,54 Another potentialCOX-independent mechanism is theplatelet activating factor (PAF) pathway.PAF mediates inflammatory states un-affected by NSAIDs and is elevated in themenstrual effluent of women withNSAID-resistant dysmenorrhea.52 Al-terations in PAF synthesis were found inwomen with endometriosis.55,56 In a


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mouse model, we recently confirmed aPAF receptor agonist is capable ofincreasing uterine hypercontractility andimpairing perfusion, causing uterinehypoxemia and pain.23 The effects onuterine physiology were blocked with aPAF receptor antagonist in our mousemodel, but PAF-targeting treatmentshave not yet been conducted in womenwith dysmenorrhea. Additional researchis needed to elucidate the possible rolesof leukotrienes and PAF in NSAID-resistant dysmenorrhea.

Peripheral and central sensitizationwithin dysmenorrheaThe aforementionedmolecules are readilyimplicated in mechanisms that wouldincrease peripheral nerve sensitivity. PGcan sensitize primary afferents57 via themodulation of tetrodotoxin-resistant so-dium channels58 and transient receptorpotential vanilloid 1 receptors.59 Localneurogenesis is another element of pe-ripheral sensitization, and was demon-strated to contribute to secondarydysmenorrhea.32,60-62 However, the roleof local neurogenesis in NSAID-resistantdysmenorrhea has not yet beendemonstrated.Alternatively, widespread increases in

pain sensitivity known as central sensi-tization could contribute dysmenor-rhea.63 Although it has not beendemonstrated directly, evidence of cen-tral sensitization within dysmenorrheaincludes increased referred pain,64 andheightened experimentally evoked ther-mal, ischemic, muscular, and pressure

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pain sensitivity.65-68 Dysmenorrheicwomen also exhibit altered gray mattervolume in key cortical regulatory painregions.69-71 Since NSAIDs are notknown to affect central sensitization,72

further research is needed to confirmwhether dysfunctional central sensitiza-tion occurs in NSAID-resistantdysmenorrhea.

Mechanisms driving peripheral orcentral sensitization could also lead toincreased referred pain. In rat models,uterine inflammation led to neurogenicplasma extravasation the abdominalmusculature and adjacent organs.73,74

Although some women with dysmen-orrhea may also have superficialabdominal muscular pain, it is notpredictive of endometriosis.75 Thus, itremains unclear whether women withabdominal muscle cramps duringmenses are more or less likely torespond to NSAIDs.

The importance of medical adherenceMedication adherence likely contributesto NSAID-resistant dysmenorrhea. Aquarter to half of dysmenorrheic womendo not take the correct medication ordosage.10,12 Side effects associated withNSAIDs such as gastrointestinaldiscomfort also limit medication adher-ence.8 Along with medication type,dosage, and side effects, the timing ofNSAID administration may affect effi-cacy. Notably, biochemical analysesdemonstrated that naproxen adminis-tration prior to initiating the COX-2cascade results in nearly complete sup-pression of PG synthesis; attempting toblock synthesis afterwards only pro-duced a gradual and incomplete sup-pression.76 However, a single, butunderpowered trial, comparing men-strual pain relief between prophylactic vsabortive treatment with ibuprofen didnot find a difference.77 It is possible thatdifferences in prophylactic use of nap-roxen and ibuprofen could be due todifferent preferential binding to COX-1and COX-2 (Table). Aside from thistrial, clinical investigators have notsufficiently investigated prophylacticNSAIDs use prior to the onset ofmenses.Although an educational trial regardingprophylaxis did demonstrate increased

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patient knowledge, reduction of men-strual pain was not evaluated.78

Treatments for NSAID-resistantdysmenorrheaUntil it can be determined why somewomen with dysmenorrhea are unre-sponsive to NSAIDs, it is essential thatclinicians be aware of adequate alterna-tive treatments. Below, we present a listof candidate pharmacological and non-pharmacological treatments previouslyinvestigated for use in dysmenorrhea.We noted where generic medications areavailable, but insurance coverage for off-label use needs to be considered in termsof patient costs.

Hormone-based treatmentsHormonal treatments, specifically oralcontractive pills (OCPs), are widely usedfor NSAID-resistant dysmenor-rhea.22,79,80 OCPs thin the endometriallining, resulting in reduced COX-2 andPG production.16,81 The bulk of researchexamining OCPs and dysmenorrhea fo-cuses on the effect of different hormonalregimens and combinations. A system-atic review suggested continuous regi-mens are generally more effective atreducing dysmenorrhea symptoms thancyclic regimens.82 Cyclic regimens oftenimprove dysmenorrhea, but studiesrarely found differences betweendifferent hormone combinations.83

Nomegestrol acetate/17b-estradiol wasmore effective in treating menstrual painwhen compared to drospirenone/ethi-nylestradiol oral contraceptive.84 Acomparison of 20 mg ethinyl estradiol/150 mg desogestrel to 20 mg ethinylestradiol/100 mg levonorgestrel sug-gested each improved dysmenorrheasimilarly (23% and 26% of women,respectively).85 Combination OCPs withestradiol valerate/dienogest and ethinylestradiol/levonorgestrel both reducedexperienced time of dysmenorrhea painby 4 days, but significant differencesbetween the regimens were notobserved.86 A systematic reviewconcluded that levonorgestrel-releasingintrauterine devices are as effective asOCPs at alleviating menstrual pain.87 Acritical limitation of the above studies ofcomparing hormonal regimens and

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combinations in primary dysmenorrheais that they have not specifically evalu-ated their utility in NSAID-resistantdysmenorrhea.Hormonal treatments are also used

for women with secondary dysmenor-rhea unresponsive to NSAIDs and whodo not wish to undergo surgery. A ran-domized placebo-controlled trialdemonstrated that OCPs were an effec-tive treatment for secondary dysmenor-rhea associated with endometrosis.88

Continuous OCP regimens improvedysmenorrhea better than cyclical regi-mens after surgery for endometriosis,89

although there are concerns that theestradiol component of OCPs couldexacerbate endometriosis.90 In any case,hormonal suppression is still recom-mended for treatment of dysmenorrheain current consensus guidelines.91

Other studies on secondary dysmenor-rhea treatment focused on gonadotropin-releasing hormone (GnRH) agonists. Arandomized placebo-controlled trialshowed GnRH agonist leuprolide almostcompletely eliminated menstrual pain in44 patients with suspected endometri-osis.92 Although effective in treating sec-ondary dysmenorrhea, GnRH agonist-induced reduction of estrogen promotesbone density loss over time.93,94 PairingGnRH agonists with add-back orreplacement estrogen therapy95-97 or uti-lizing low GnRH agonist dosages98 arecapable of alleviating menstrual painassociated with endometriosis withoutbone loss. The utilization of these drugs isrecommended by the American Societyfor ReproductiveMedicine guidelines onlyafter laparoscopic diagnosis of endome-triosis, given these risks.99 Alongside itsside-effect profile, patients may findmonthly injections of GnRH agonistsinconvenient.A recent review suggested that oral

progestins may be a better first-line op-tion for menstrual and pelvic pain asso-ciated with endometriosis.90 Oralprogestins such as norethindrone acetateand dienogest target the progesteronereceptor, and have regulatory approvalfor endometriosis. A randomizedplacebo-controlled trial demonstratedthat dienogest reduced dysmenorrhea inwomen with endometriosis.100

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Dienogest was also as effective inreducing menstrual pain whencompared to the GnRH agonist leupro-lide.101 An open-label study foundnorethindrone acetate was as effective atreducing menstrual pain as OCPs.102

Despite their efficacy, it is important toconsider the frequent irregular bleedingassociated with oral progestins.103

Although a meta-analysis supports oralprogestin usage for endometriosis,104 itremains to be investigated whether it isan effective empirical option for NSAID-resistant dysmenorrhea.

Another class of hormonal treatmentused for secondary dysmenorrhea isaromatase inhibitors.105 Aromatase is anenzyme that is expressed in the ovarianfollicle and endometriotic stromal cellsand converts androgens to estrogen.106

Aromatase inhibitors, primarily used toreduce endometriomas107 and my-omas108 in women, may be beneficial forsecondary dysmenorrhea by renderingpatients amenorrheic. Due to concernregarding its effects on bone mineraldensity and other adverse side effects,add-back regimens may be necessary.109

Further research is needed to determineif aromatase inhibitors are Qappropriateof NSAID-resistant dysmenorrhea.

Surgical interventionsAlthough excision of endometriotic le-sions are routinely recommended,99 somesymptomatic patients who do not haveidentified anatomical factors followingdiagnostic surgical evaluation may benefitfrom alternative surgical strategies. Lapa-roscopic uterine nerve ablation (LUNA)and laparoscopic presacral neurectomy(PSN) are 2 surgical interventions histor-ically employed for the treatment of sec-ondary dysmenorrhea (reviewed byProctor and colleagues110 and Latthe andcolleagues111). However, a large multisiterandomized controlled trial conducted byDaniels and colleagues112 determined thatLUNA for chronic pelvic pain did not havea significant effect on dysmenorrhea,regardless of time accrued following sur-gery, and led to this procedure largely be-ing abandoned. However, this trial andmany of the other negative trials did notstudy the effects of LUNA or PSN inNSAID-resistant dysmenorrhea inwomen


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without chronic pelvic pain andendometriosis.

Clinical trials examined the efficacy ofsurgical interventions on primarydysmenorrhea. A double-blinded ran-domized controlled trial of LUNAdemonstrated menstrual pain relief in halfof womenwith primary dysmenorrhea.113

A trial comparing LUNA and LUNA plusPSN reported 69% and 73% of primarydysmenorrhea patients, respectively, hadimprovements inmenstrual pain.114 Chenand Soong115 found that 77% of primarydysmenorrhea patients benefited fromPSN. Although it is unknown whetherthese patients with primary dysmenorrheawere NSAID-resistant, it is quite possiblethat surgery was performed since NSAIDmanagement was not feasible. Thus,further research is needed to clarify theutility of LUNA and PSN as treatments forNSAID-resistant dysmenorrhea, particu-larly in the absence of endometriosis andchronic pelvic pain.

VasodilatorsAnother potential treatment fordysmenorrhea is sildenafil citrate. Sil-denafil specifically blocks cyclic guano-sine monophosphate degradation, thuspromoting smooth muscle relaxation inthe uterus and surrounding bloodvessels.116 In a randomized placebo-controlled trial, sildenafil reduced men-strual pain in women with primarydysmenorrhea.117 Similar to sildenafil,nitric oxide donor drugs also promotevasodilation and myometrial musclerelaxation, and are capable of reducingmenstrual pain. Transdermal nitroglyc-erin or glyceryl trinitrate administrationon the first day of menstruation was suf-ficient to reduce reported menstrual painfor the duration ofmenses.118,119Glyceryltrinitrate andnitroglycerin are available asgeneric medications. A limiting factor ofglyceryl trinitrate and similar vasodilatorsare their side effects that impair tolera-bility including headaches.120 Therefore,the utility of glyceryl trinitrate or othervasodilators for NSAID-resistantdysmenorrhea remains to be determined.

Calcium channel blockersCalcium channel blockers, available asgeneric medications, are primarily


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indicated to treat hypertension byreducing contractility in vascular smoothmuscle and cardiac muscles; they alsoinhibit uterine contractions in pregnantand nonpregnant women.121 Observa-tional studies from the late 1970sdemonstrated that 20-40 mg of calciumchannel blocker nifedipine providedmenstrual pain relief but was associatedwith side effects such as tachycardia,flushing, and headache.122,123 Thesefindings are supported in a controlledtrial showing that 14 of 19 patients ob-tained menstrual pain relief with nifedi-pine.124 Although one research studysuggested efficacy of nifedipine inwomenunresponsive to salicylates,125 futureresearch is needed to establish efficacy forwomen unresponsive to NSAIDs.

Vasopressin and oxytocin receptorantagonistsVasopressin and oxytocin, hormonesknown to stimulate myometrial con-tractions, were also implicated in pri-mary dysmenorrhea.126 There isconflicting evidence, however, on theeffects of vasopressin/oxytocin receptorantagonists on dysmenorrhea. Severalstudies showed that vasopressin-inducedcontractions in dysmenorrheic womenwere reduced by vasopressin/oxytocinreceptor antagonists atosiban127,128 andSR49059.129 In contrast, Valentin andcolleagues130 demonstrated that whencompared to healthy controls, dysmen-orrheic women did not show elevatedlevels of vasopressin and that the intra-venous administration of atosiban didnot attenuate menstrual pain or uterinecontractility. It is important to note thatthe study of Valentin and colleagues130

administered atosiban intravenously af-ter menses onset, while the study ofBrouard et al129 administered SR49059orally at least 4 hours prior to mensesonset. Thus, more evidence is needed toexamine how the time and type ofadministration impacts the efficacy ofvasopressin/oxytocin receptor antago-nists on NSAID-resistant dysmenorrhea.

AntispasmodicsAlthough infrequently used in theUnited States, antispasmodics such ashyoscine butylbromide are used globally

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to treat abdominal pain, includingmenstrual pain. Hyoscine butylbromideis an anticholinergic drug that targetsmuscarinic receptors to relax smoothmuscle.131 In the United States, a similardrug, hyoscyamine sulfate, is available asa generic medication. Common adverseeffects include dry mouth, constipation,and dizziness. Although it is frequentlyprescribed for visceral spasms, it is notFood and Drug Administration indi-cated for dysmenorrhea.

In a double-blind crossover study,Kemp132 demonstrated that hyoscinebutylbromide was just as effective asaspirin in treating dysmenorrhea.Questionnaire-based studies showedthat women used hyoscine butylbromideto self-treat their dysmenorrhea with asimilar frequency as paracetamol andNSAIDs.133-136 A randomized controlledtrial compared a combination of anantispasmodic (drotaverine) and NSAID(aceclofenac) vs aceclofenac alone, andfound the combination provided supe-rior pain relief for primary dysmenor-rhea.137 Since the addition of drotaverineprovided better pain relief than aceclo-fenac alone, these results support the useof an adjunct antispasmodic to treat re-fractory menstrual pain. These findingsalso suggest that muscle spasm pain indysmenorrhea may contribute toNSAID-resistant pain.

Complementary andnonpharmacological medicaltreatmentsHerbal and dietary supplements wereproposed as alternative treatments fordysmenorrhea. Although many varietiesare currently used to treat dysmenorrhea,inconsistencies between various studiesmake it difficult to determine the efficacyof supplements (reviewed by Pattanittumand colleagues138). Ginger, the mostcommonly reported effective remedy inrandomized controlled trials, onlyreduced pain 1.5 cm on a 10-cm visualanalog scale.139 Thus, more high-qualitytrials demonstrating superior effective-ness of herbal and dietary supplementsare needed to provide viable options forpatients unresponsive to NSAIDs.

Many nonpharmacological remediesfor dysmenorrhea were investigated.

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Limited evidence suggests acupunc-ture,140 hot water bottles,141 yoga,142

massage,143 physiotherapy,144 and exer-cise145 may be helpful formenstrual pain,but as with many traditional pharma-ceuticals, effects were not consistentlyrepeated or verified with large random-ized controlled trials. In contrast, trans-cutaneous electrical nerve stimulation(TENS) was shown to reduce menstrualpain in several randomized146-148 andobservational149,150 trials. Since trans-abdominal application of TENS has noeffect on uterine contractility,25 TENSmay affect associated abdominal musclecontractility instead. The role of abdom-inal muscle cramping in dysmenorrheawould be consistent with the utility ofantispasmodic agents described above.The findings obtained with TENS areconsistent with the hypothesis that PG-independent pathways contribute todysmenorrhea, and suggest that theattenuation of these alternative pathwaysmay be effective.

Future directionsAs mentioned above, most studiesinvestigating various treatments fordysmenorrhea have not examined theprevalence of NSAID resistance amongtheir participants. Since dysmenorrheapatients may choose treatments based onpreference rather than previous NSAIDtreatment failure, the overall efficacy oftreatments for NSAID-resistant dysmen-orrhea is unknown. Validated electronictools that track menstrual pain and theuse of rescue medication151 would beuseful for clinical trials. It is likely thatmultiple phenotypes of dysmenorrheaexist reflecting different underlying cau-ses. However, since the abandonment ofclassifying spasmodic and congestivemenstrual pain phenotypes,152 areplacement classification scheme wasnot popularly accepted, and shouldpossibly be reconsidered for the diagnosisfor NSAID-resistant dysmenorrhea.

Pharmacological and gene assays couldhelp identify forms of NSAID-resistantdysmenorrhea that may respond toalternative treatment strategies. A similarresearch strategy revolutionized the un-derstanding of aspirin resistanceobserved in antiplatelet therapy. The

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utilization of ex-vivo assays that detectmechanisms of aspirin resistance led tothe identification of polymorphisms,43,44

absorption impairments,153 or otherfactors that limit drug bioavail-ability.46,154 The translation of these testsfor NSAID-resistant pain could similarlyclarify why some patients are unrespon-sive and provide avenues for adequatetherapeutic development.

ConclusionA significant proportion of women withdysmenorrhea obtain no relief fromNSAIDs. Opportunities to characterizeNSAID resistance with diagnostic testingand enroll women with resistance phe-notypes into novel clinical trials were notpursued. We suggest that future studiesexplore molecular targets that couldexplain resistance and evaluate noveltherapies in these patients. Given thatCOX are implicated in other acute (eg,muscle soreness, inflammation, burnpain) and chronic (eg, migraine,arthritis) pain conditions, studying themechanisms of NSAID resistance has thebroad potential to improve pain relief inpatients with multiple types of refractorypain conditions.Prior treatment algorithms suggest

that symptomatic patients with NSAID-resistant dysmenorrhea who do notrespond to OCPs undergo diagnosticlaparoscopic examination.22,79 Recentconsensus guidelines suggest trials oflevonorgestrel-releasing intrauterine de-vices, with surgery being the last diag-nostic and therapeutic option.91

Although surgery for symptomatic pa-tients is often effective and recom-mended,155-157 some patientsmay be notwilling to undergo surgery. For thesepatients, until research establishes theunderlying mechanisms, some of theoptions described here could partiallyameliorate their unremitting monthlypain. -

ACKNOWLEDGMENT

Wewould like to thank Dr Gerald Gebhart for hisassistance with the manuscript.

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